Nuclear hormone receptors (NHRs) constitute a super-family of ligand-dependent and sequence-specific transcription factors. Members of the NHR family influence transcription either directly via specific binding to promoter target genes, or indirectly via protein-protein interactions with other transcription factors. The NHR family includes, for example, conventional NHRs, such as, for example, cortisol, aldosterone, estrogen, progesterone, testosterone, dihydrotestosterone, vitamin D3, thyroid hormone, and retinoic acid; and orphan NHRs that either interact with ubiquitous ligands that have not been identified, or do not need to bind ligand to exert activity.
Steroid binding NHRs (SB-NHRs) are a sub-family of NHRs that utilize steroid based ligands. Exemplary SB-NHRs include, but are not limited to, for example, the androgen receptor (AR); the estrogen receptor (ER); the progesterone receptor (PR); the glucocorticoid receptor (GR); the mineralocorticoid receptor (MR); the aldosterone receptor (ALDR); and the steroid and xenobiotic receptor (SXR).
In general, the endogenous ligands that bind to SB-NHRs have a common steroid core. Exemplary endogenous ligands, include, but are not limited to, for example, cortisol, aldosterone, estrogen, progesterone, testosterone, and dihydrotestosterone. The specificity with which an endogenous ligand binds to a particular SB-NHR depends on the differential substitution about the steroid core of such ligand.
Non-endogenous ligands, such as, for example, synthetically or food derived steroidal or non-steroidal SB-NHR antagonists and/or agonists have been developed to treat a variety of medical conditions. Synthetically derived SB-NHR antagonists and/or agonists include, but are not limited to, for example, RU486, which is an agonist of the PR; flutamide, which is an antagonist of the AR; and tamoxifen, which is a partial agonist/partial antagonist of the ER. Food-derived SB-NHR antagonists and/or agonists include, but are not limited to, for example, flavanoid phytoestrogens found in soy.
Non-endogenous SB-NHR antagonists and/or agonists can be synthetically engineered by first identifying a core structure capable of mimicking the core system of the endogenous ligand of interest, and subsequently differentially substituting about the core of the mimic to obtain an agent with selectivity for the SB-NHR of interest. Differential substitution about the steroid mimic core can result in a series of high affinity agonists and antagonists with specificity for, for example, ER versus PR versus AR versus GR versus MR.
The sultam compounds disclosed herein may mimic at least one endogenous ligand capable of binding to at least one SB-NHR and/or at least one other NHR, and therefore may be useful to modulate the function of at least one SB-NHR and/or at least one other NHR.